Abstract W P116: Cerebrovascular and Alzheimer’s Pathologies Combined in Mouse Models of Mixed Dementia Alter the Progression of Memory Impairment and Disease

• Published in: Stroke (1970) 2015-02, Vol.46 (suppl_1)
• Main Authors: Brothers, Holly, Phillips, Oliver W, Latta, Clare H, Sudduth, Tiffany L, Braun, Kaitlyn, Wilcock, Donna M
• Format: Article
• Language: English
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/str.46.suppl_1.wp116

Abstract only Dementia is most often attributed to Alzheimer’s disease (~70%) or vascular dementia (~17%), yet 20-50% of dementia cases share aspects of both. Better understanding of dementias within this spectrum can improve diagnosis, inform interpretation of clinical data confounded by co-morbidity, and direct therapeutic approaches. We hypothesized that combined pathologies alter the time-course of memory impairment and the expression of primary disease pathology. We compared and combined aspects of cerebrovascular disease (chronic cerebral hypoperfusion) and Alzheimer’s disease (transgene-driven tau or amyloid pathology). We induced chronic cerebral hypoperfusion by wrapping each common carotid artery with a microcoil that remains in situ and reduces cerebral blood flow to approximately 80%; a procedure called bilateral carotid artery stenosis (BCAS). To create conditions of mixed dementia, we performed BCAS in two transgenic models of Alzheimer’s pathology; the rTg4510 which overexpresses mutant human tau, and APP/PS1 that develops ß-amyloid pathology. Transgenic mice and their wildtype littermates received BCAS or sham surgeries near the onset of pathology survived 1 or 6 months, or during advanced pathology and survived 1 month. This generated 12 experimental groups (n of 4-11 each). We evaluated spatial memory impairment, neuroimmune phenotype, white matter integrity, tau pathology and ß-amyloid pathology. The progression of memory impairment and disease pathology is altered in the mixed dementia models, and these changes are relative to the age of onset and duration of hypoperfusion. For example, hypoperfusion has a larger impact on spatial memory impairment in aged APP/PS1 mice. Additionally, BCAS reduced the expression of CD86, an immune marker associated with a de-activated immune state, only in rTg4510 mice. These findings highlight changes in the time-course of cognitive impairment and pathology that might be expected in the substantial clinical population with co-morbid vascular and Alzheimer’s dementias.